Ovarian Cancer is the fifth leading cause of death from all cancers. Platinum-based chemotherapy is the primary treatment for ovarian cancer. However, the majority of ovarian cancer patients eventually relapses and becomes refractory to additional treatment. This drug resistance is a major impediment to the successful treatment of ovarian cancer today. Many proposed mechanisms of drug resistance have been suggested, but to date, the mechanisms of drug resistance remain unclear. To elucidate the underlying mechanisms in which drug resistance develops in ovarian cancer cells, global protein expression pattern changes in drug-sensitive and -resistant ovarian cancer cells need to be established. The objective of this study is to understand the mechanism by which cisplatin drug resistance occurs in ovarian cancer through the use of proteomics technologies. It is hypothesized that cisplatin resistance is a multifactorial event and involves many biological pathways and proteins involved in these pathways. Our long term goal is to find the drug targets and by modulating these targets, we can sensitize cisplatin resistant ovarian cancer cells. The Aim 1 of this project is to validate a panel of potential biomarkers of cisplatin resistance as determined by a LC/MS-based label-free protein quantification experiment. These differentially expressed proteins will be validated using multiple reaction monitoring (MRM) and/or protein microarray approaches before being selected as potential biomarkers. In Aim 2, we will try to modulate the expression of a panel of the selected potential biomarkers by using small molecule inhibitors and/or the siRNA approach, as needed, to reverse cisplatin resistance. Through this proposed research project, we expect that discovery of biomarkers of cisplatin resistance and modulation of these biomarkers in ovarian cancer cells will be valuable for the future of improving therapeutics and drug discovery. [unreadable] [unreadable] [unreadable]